Process for preparing substituted pyridines

ABSTRACT

A process for preparing a compound of the formula                    
     wherein n, R 1 , R 2 , R 3  and X are as defined above, used as an intermediate in the synthesis of β-adrenergic receptor agonists.

CROSS REFERENCE TO RELATED APPLICATION

This non-provisional application is based upon and claims priority fromU.S. provisional application No. 60/193,772, filed Mar. 31, 2000.

BACKGROUND OF THE INVENTION

The present invention relates to a process for preparing substitutedpyridines which are intermediates in the synthesis of β-adrenergicreceptor agonists useful as hypoglycemic and antiobesity agents,increasing lean meat deposition and/or improving the lean meat to fatratio in edible animals. The β-adrenergic receptor agonists furtherpossess utility in the treatment of intestinal motility diseasedisorders, depression, prostate disease, dyslipidemia and airwayinflammatory disorders such as asthma and obstructive lung disease.

The disease diabetes mellitus is characterized by metabolic defects inproduction and/or utilization of carbohydrates which result in thefailure to maintain appropriate blood sugar levels. The result of thesedefects is elevated blood glucose or hyperglycemia. Research in thetreatment of diabetes has centered on attempts to normalize fasting andpostprandial blood glucose levels. Current treatments includeadministration of exogenous insulin, oral administration of drugs anddietary therapies.

Two major forms of diabetes mellitus are recognized. Type I diabetes, orinsulin-dependent diabetes, is the result of an absolute deficiency ofinsulin, the hormone which regulates carbohydrate utilization. Type IIdiabetes, or non-insulin dependent diabetes, often occurs with normal,or even elevated levels of insulin and appears to be the result of theinability of tissues to respond appropriately to insulin. Most of theType II diabetics are also obese.

The β-adrenergic receptor agonists effectively lower blood glucoselevels when administered orally to mammals with hyperglycemia ordiabetes.

The β-adrenergic receptor agonists also reduce body weight or decreaseweight gain when administered to mammals. The ability of β-adrenergicreceptor agonists to affect weight gain is due to activation ofβ-adrenergic receptors which stimulate the metabolism of adipose tissue.

β-Adrenergic receptors have been categorized into β₁-, β₂- andβ₃-subtypes. Agonists of β-receptors promote the activation of adenylcyclase. Activation of β₁-receptors invokes increases in heart ratewhile activation of β₂-receptors induces relaxation of skeletal muscletissue which produces a drop in blood pressure and the onset of smoothmuscle tremors. Activation of β₃-receptors is known to stimulatelipolysis (the breakdown of adipose tissue triglycerides to glycerol andfree fatty acids) and metabolic rate (energy expenditure), and therebypromote the loss of fat mass. Compounds that stimulate β-receptors are,therefore, useful as anti-obesity agents, and can also be used toincrease the content of lean meat in edible animals. In addition,compounds which are β₃-receptor agonists have hypoglycemic and/oranti-diabetic activity, but the mechanism of this effect is unknown.

Until recently β₃-adrenergic receptors were thought to be foundpredominantly in adipose tissue. β₃-Receptors are now known to belocated in such diverse tissues as the intestine (J. Clin. Invest., 91,344 (1993)) and the brain (Eur. J. Pharm., 219,193 (1992)). Stimulationof β₃-receptors have been demonstrated to cause relaxation of smoothmuscle in colon, trachea and bronchi. Life Sciences, 44(19), 1411(1989); Br. J. Pharm., 112, 55 (1994); Br. J. Pharmacol, 110, 1311(1993). For example, stimulation of β₃-receptors has been found toinduce relaxation of histamine-contracted guinea pig ileum, J. Pharm.Exp. Ther., 260, 1, 192 (1992).

The β₃-receptor is also expressed in human prostate. Because stimulationof β₃-receptors cause relaxation of smooth muscles that have been shownto express the β₃-receptor (e.g. intestine), one skilled in the artwould predict relaxation of prostate smooth muscle. Therefore,β₃-agonists will be useful for the treatment or prevention of prostatedisease.

SUMMARY OF THE INVENTION

The present invention relates to a process for preparing a compound ofthe formula

wherein n is 0, 1, 2 or 3;

R¹ is hydrogen or halo;

each R² is independently hydrogen, halo, trifluoromethyl, cyano, SR⁴,OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ or NR⁴CO₂ R⁴;

R³ is tetrahydrofuranyl, tetrahydropyranyl or a silyl protecting group;

X is halo, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy,m-nitrobenzenesulfonyloxy or p-nitrobenzenexulfonyloxy;

R⁴ and R⁵, for each occurrence, are each independently selected from

hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein thearyl, heterocycloalkyl and heteroaryl groups are optionally substitutedby one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

comprising reacting a compound of the formula

wherein n, R¹, R² and X are as defined above, with a silyating agent inthe presence of a base.

The term “alkyl”, as used herein, as well as the alkyl moieties of othergroups referred to herein (e.g., alkoxy), may be linear or branched, andthey may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl) or be linear or branched and contain cyclicmoieties. Unless otherwise indicated, halogen includes fluorine,chlorine, bromine, and iodine.

The term “halo”, as used herein, unless otherwise indicated, includesfluoro, chloro, bromo or iodo.

(C₂-C₉)Heterocycloalkyl when used herein includes, but is not limitedto, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl,pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, etc.

(C₂-C₉)Heteroaryl when used herein includes, but is not limited to,furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl,purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl, etc.

The term “silyl protecting group”, when used herein includes, but is notlimited to, trimethylsilyl, triethylsilyl, triisopropylsilyl,dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl,tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, andt-butylmethoxyphenylsilyl.

The present invention further relates to a process wherein the silyatingagent is tert-butyldimethylsilyl chloride, triethylchlorosilane,triisopropylchlorosilane or diphenylmethylchlorosilane.

The present invention further relates to a process wherein the base istriethylamine, N,N-diisopropylethylamine, imidazole, pyridine,2,6-lutidine or N-methylmorpholine.

The present invention further relates to a process wherein the compoundof the formula

is formed by reacting a compound of the formula

wherein n, R¹ and R² are as defined above, with a sulfonyl chloride inthe presence of a base, and in the case wherein X is halo, by furthertreatment with a metal halide.

The present invention further relates to a process wherein the sulfonylchloride is p-toluenesulfonyl chloride, methanesulfonyl chloride,m-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride orbenezenesulfonyl chloride.

The present invention further relates to a process wherein the base istriethylamine, diisopropylethylamine, pyridine, 2,4,6-collidine or2,6-lutidine.

The present invention further relates to a process wherein the metalhalide is lithium chloride.

The present invention further relates to a process wherein the compoundof the formula

is formed by reacting a compound of the formula

wherein n, R¹ and R² are as defined above, with a dihydroxylating agent,with or without a co-oxidant and/or a coordinating ligand.

The present invention further relates to a process wherein thedihydroxylating agent is osmium tetroxide or potassium permanganate.

The present invention further relates to a process wherein theco-oxidant is potassium ferricyanide, hydrogen peroxide, tert-butylhydroperoxide or N-methylmorpholine-N-oxide.

The present invention further relates to a process wherein thecoordinating ligand is hydroquinidine 1,4-phthalazinediyl diether orhydroquinine 1,4-phthalazinediyl diether.

The present invention further relates to a process wherein the compoundof the formula

is formed by reacting a compound of formula V

wherein n, R¹ and R² are as defined above, with a methylating reagent.

The present invention further relates to a process wherein themethylating reagant is prepared from methyltriphenylphosphonium bromideand potassium tert-butoxide.

The present invention further relates to a process wherein the compoundof the formula

is formed by reducing a compound of the formula

wherein n, R¹ and R² are as defined above, with a reducing agentfollowed by hydrolysis with an acid or base.

The present invention further relates to a process wherein the reducingagent is diisobutylaluminum hydride.

The present invention further relates to a process wherein the acid issulfuric acid.

The present invention relates to a process for preparing a compound ofthe formula

wherein n is 0, 1, 2 or 3;

R¹ is hydrogen or halo;

each R² is independently hydrogen, halo, trifluoromethyl, cyano, SR⁴,OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

R³ is tetrahydrofuranyl, tetrahydropyranyl or a silyl protetcting group;

X is halo, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy,m-nitrobenzenesulfonyloxy or p-nitrobenzenexulfonyloxy;

R⁴ and R⁵ are each independently selected from hydrogen, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl or (C₁-C₆)alkoxy;

or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above; and

comprising

(a) reacting a compound of the formula

wherein n, R¹ and R² as defined above, with a reducing agent followed byhydrolsis with an acid or base;

(b) reacting the intermediate of formula XIII so formed

wherein n, R¹ and R² are as defined above, with a methylating agent toform a vinylpyridine compound of the formula

(c) reacting the vinylpyridine compound so formed in step (b) with adihydroxylating agent, with or without a co-oxidant and/or acoordinating ligand to form a compound of the formula

wherein n, R¹ and R² are as defined above;

(d) reacting the compound of formula XI so formed with a sulfonylchloride in the presence of a base to form a compound of the formula X

wherein n, R¹, R² and X are as defined above; and

(e) reacting the compound of formula X so formed with silyating agent inthe presence of a base.

The present invention relates to a process for preparing a compound ofthe formula

wherein n is 0, 1, 2 or 3;

each R² is independently hydrogen, halo, trifluoromethyl, cyano, SR⁴,OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ or NR⁴CO₂ R⁴;

R⁴ and R⁵, for each occurrence, are each independently selected fromhydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein thearyl, heterocycloalkyl and heteroaryl groups are optionally substitutedby one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and

Y is

wherein:

Q¹ is oxygen, nitrogen or sulfur;

Q² is carbon or nitrogen;

Q³ is hydrogen, —(CH₂)_(q)-phenyl, —(C₁-C₁₀)alkyl, —(CH₂)_(q)—NG¹G²,—(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or a heterocycleselected from the group consisting of —(CH₂)_(q)-pyridyl,—(CH₂)_(q)-pyrimidyl, —(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-(1,2,4-oxadiazolyl), —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl;

wherein one of the ring nitrogen atoms of said —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl may optionally besubstituted by (C₁-C₈)alkyl optionally independently substituted withone or more halo atoms;

wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms, nitro,cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G²,—(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl and—(CH₂)_(q)—SO₂NG¹G²;

wherein the phenyl moiety of said —(CH₂)_(q)-phenyl may optionally besubstituted with one or more substituents independently selected fromthe group consisting of (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms, hydroxy, (C₁-C₆)alkoxyoptionally independently substituted with one or more halo atoms,(C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro,—(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³,—(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G²;—(CH₂)_(q)—NG³—SO₂—G³ and —(CH₂)_(q)—NG³—SO₂—NG¹G²;

Q⁴ is —(CH₂)_(q)—CN, —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², —(CH₂)_(q)CH₂OH,—(CH₂)_(q)—CHO, —(CH₂)_(q)—CO—G³, —(CH₂)_(q)—CONG¹G², or a heterocycleselected from —(CH₂)_(q)-thiazolyl, —(CH₂)_(q)-oxazolyl,—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl,—(CH₂)_(q)-1,2,4-oxadiazolyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl;

wherein one of the ring nitrogen atoms of said —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl may optionally besubstituted by (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—CO₂G³, halo, nitro, cyano,—(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²;

Q⁵ is hydrogen or (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

Q⁶ is a covalent bond, oxygen or sulfur;

Q⁷ is hydrogen or (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NH orN—(C₁-C₆)alkyl;

Q¹⁰ is nitro, amino, (C₂-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl,(CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR¹³, (CH₂)_(q)SO₂NR¹¹R¹²,(CH₂)_(q)—NR¹¹SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹),(CH₂)_(q)—O—(CH₂)_(p)CO₂H, (CH₂)_(q)—O—(CH₂)_(p)COR¹³,(CH₂)_(q)—O—(CH₂)_(p)P(O)(OR⁸)(OR⁹), (CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R¹², or(CH₂)_(q)—O—(CH₂)_(p)—NR¹¹SO₂R¹⁰;

R⁸ and R⁹ are each independently hydrogen or (C₁-C₆)alkyl; and

wherein G¹ and G² for each occurrence are each independently hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more halo,(C₁-C₈)alkoxy(C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, or G¹ and G² togetherwith the nitrogen to which they are attached form a saturatedheterocyclic ring having from 3 to 7 carbon atoms wherein one of saidcarbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;

G³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

R¹⁰ for each occurrence is independently (C₁-C₆)alkyl or(C₁-C₆)alkoxy(C₁-C₆)alkyl;

R¹¹ and R¹² are taken separately and, for each occurrence, areindependently hydrogen, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or(C₁-C₆)alkoxy(C₁-C₆)alkyl, or

R¹¹ and R¹² are taken together with the nitrogen atom to which they areattached and form a pyrrolidine, piperidine or morpholine ring whereinsaid pyrrolidine, piperidine or morpholine may optionally be substitutedat any carbon atom by (C₁-C₄)alkyl or (C₁-C₄)alkoxy;

R¹³ for each occurrence is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, NR¹¹R¹², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkylwherein R¹¹ and R¹² are as defined above;

R¹⁴ and R¹⁵ are each independently hydrogen, halo, (C₁-C₆)alkyl, nitro,cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹R¹², COR¹³, CO₂R¹¹,(C₁-C₆)alkoxy, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹ or OR¹¹;

p for each occurrence is independently an integer of 1 to 6; and

q for each occurrence is independently 0 or an integer of 1 to 6;

with the proviso that when Q⁹ is O or S then n is not 0;

with the proviso that when Q¹ is oxygen or sulfur then Q³ is absent; and

with the proviso that when Q² is nitrogen then Q⁵ is absent;

comprising reacting a compound of the formula

wherein n, R², R⁶ and Y are as defined above; and

R³ is tetrahydrofuranyl, tetrahydropyranyl or a silyl protetcting group;with tetra-n-butylammonium fluoride.

The present invention further relates to a process wherein a compound ofthe formula

wherein n, R², R³, R⁶ and Y are as defined above, is formed by treatinga compound of the formula

wherein R¹ is halo and wherein n, R², R³, R⁶ and Y are as defined above,with ammonium formate in the presence of palladium on carbon.

The present invention further relates to a process wherein a compound ofthe formula

is formed by reacting a compound of the formula

wherein R¹ is hydrogen or halo and wherein n, R², R³ and Y are asdefined above with an organic acid anhydride, a dicarbonate or anorganic acid chloride.

The present invention further relates to a process wherein thedicarbonate is di-tert-butyl dicarbonate

The present invention further relates to a process wherein a compound ofthe formula

is formed by reacting the compound

wherein n, R¹, R², R³ and X are as defined above, with an amine of theformula H₂NY, wherein Y is as defined above, in the presence ofN,N-diisopropylethylamine.

The present invention relates to a process for preparing a compound ofthe formula

wherein n is 0, 1, 2 or 3;

each R² is independently hydrogen, halo, trifluoromethyl, cyano, SR⁴,OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

R⁴ and R⁵, for each occurrence, are each independently selected fromhydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein thearyl, heterocycloalkyl and heteroaryl groups are optionally substitutedby one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁—C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and

Y is

wherein:

Q¹ is oxygen, nitrogen or sulfur;

Q² is carbon or nitrogen;

Q³ is hydrogen, —(CH₂)_(q)-phenyl, —(C₁-C₁₀)alkyl, —(CH₂)_(q)—NG¹G²,—(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or a heterocycleselected from the group consisting of —(CH₂)_(q)-pyridyl,—(CH₂)_(q)-pyrimidyl, —(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-(1,2,4-oxadiazolyl), —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl;

wherein one of the ring nitrogen atoms of said —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl may optionally besubstituted by (C₁-C₈)alkyl optionally independently substituted withone or more halo atoms;

wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms, nitro,cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G²,—(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl and—(CH₂)_(q)—SO₂NG¹G²;

wherein the phenyl moiety of said —(CH₂)_(q)-phenyl may optionally besubstituted with one or more substituents independently selected fromthe group consisting of (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms, hydroxy, (C₁-C₆)alkoxyoptionally independently substituted with one or more halo atoms,(C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro,—(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³,—(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G²;—(CH₂)_(q)—NG³—SO₂—G³ and —(CH₂)_(q)—NG³—SO₂—NG¹G²;

Q⁴ is —(CH₂)_(q)—CN, —(CH₂)_(q)CO₂G³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², —(CH₂)_(q)CH₂OH,—(CH₂)_(q)—CHO, —(CH₂)_(q)—CO—G³, —(CH₂)_(q)—CONG¹G², or a heterocycleselected from —(CH₂)_(q)-thiazolyl, —(CH₂)_(q)-oxazolyl,—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl,—(CH₂)_(q)-1,2,4-oxadiazolyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl;

wherein one of the ring nitrogen atoms of said —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl may optionally besubstituted by (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—CO₂G³, halo, nitro, cyano,—(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²;

Q⁵ is hydrogen or (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

Q⁶ is a covalent bond, oxygen or sulfur;

Q⁷ is hydrogen or (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NH orN—(C₁-C₆)alkyl;

Q¹⁰ is nitro, amino, (C₂-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl,(CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR¹³, (CH₂)_(q)SO₂NR¹¹R¹²,(CH₂)_(q)NR¹¹SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹), (CH₂)_(q)—O—(CH₂)_(p)CO₂H,(CH₂)_(q)—O—(CH₂)_(p)COR¹³, (CH₂)_(q)—O—(CH₂)_(p)P(O)(OR⁸)(OR⁹),(CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R¹², or (CH₂)_(q)—O—(CH₂)_(p)—NR¹¹SO₂R¹⁰;

R⁸ and R⁹ are each independently hydrogen or (C₁-C₆)alkyl; and

wherein G¹ and G² for each occurrence are each independently hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more halo,(C₁-C₈)alkoxy(C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, or G¹ and G² togetherwith the nitrogen to which they are attached form a saturatedheterocyclic ring having from 3 to 7 carbon atoms wherein one of saidcarbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;

G³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

R¹⁰ for each occurrence is independently (C₁-C₆)alkyl or(C₁-C₆)alkoxy(C₁-C₆)alkyl;

R¹¹ and R¹² are taken separately and, for each occurrence, areindependently hydrogen, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or(C₁-C₆)alkoxy(C₁-C₆)alkyl, or

R¹¹ and R¹² are taken together with the nitrogen atom to which they areattached and form a pyrrolidine, piperidine or morpholine ring whereinsaid pyrrolidine, piperidine or morpholine may optionally be substitutedat any carbon atom by (C₁-C₄)alkyl or (C₁-C₄)alkoxy;

R¹³ for each occurrence is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, NR¹¹R¹², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkylwherein R¹¹ and R¹² are as defined above;

R¹⁴ and R¹⁵ are each independently hydrogen, halo, (C₁-C₆)alkyl, nitro,cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹R¹², COR¹³, CO₂R¹¹,(C₁-C₆)alkoxy, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹ or OR¹¹;

p for each occurrence is independently an integer of 1 to 6; and

q for each occurrence is independently 0 or an integer of 1 to 6;

with the proviso that when Q⁹ is O or S then n is not 0;

with the proviso that when Q¹ is oxygen or sulfur then Q³ is absent; and

with the proviso that when Q² is nitrogen then Q⁵ is absent;

comprising

(a) reacting a compound of the formula

wherein R¹ is hydrogen or halo, and n, R¹, R², R³ and X are as definedabove, with an amine of the formula H₂NY, wherein Y is as defined abovein the presence of N,N-diisopropylethylamine;

(b) reacting the compound of formula IV so formed

wherein R¹ is hydrogen or halo and wherein n, R², R³ and Y are asdefined above with an organic acid anhydride, a dicarbonate or anorganic acid chloride, to form a compound of the formula

(c) treating the compound of formula III, wherein R¹ is halo, so formedin step (b) with ammonium formate in the presence of palladium-on-carbonto form the compound of the formula

wherein n, R², R³, R⁶ and Y are as defined above, and

(d) treating the compound of formula II so formed withtetra-n-butylammonium fluoride.

The present invention relates to a process for preparing a compound ofthe formula

wherein n is 0, 1, 2 or 3;

each R² is independently hydrogen, halo, trifluoromethyl, cyano, SR⁴,OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

R⁴ and R⁵, for each occurrence, are each independently selected fromhydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and

wherein the aryl, heterocycloalkyl and heteroaryl groups are optionallysubstituted by one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and

Y is

wherein:

Q¹ is oxygen, nitrogen or sulfur;

Q² is carbon or nitrogen;

Q³ is hydrogen, —(CH₂)_(q)-phenyl, —(C₁-C₁₀)alkyl, —(CH₂)_(q)—NG¹G²,—(CH₂)_(q)—CO₂G₃, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or a heterocycleselected from the group consisting of —(CH₂)_(q)-pyridyl,—(CH₂)_(q)-pyrimidyl, —(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-(1,2,4-oxadiazolyl), —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl;

wherein one of the ring nitrogen atoms of said —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl may optionally besubstituted by (C₁-C₈)alkyl optionally independently substituted withone or more halo atoms;

wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms, nitro,cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G²,—(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl and—(CH₂)_(q)—SO₂NG¹G²;

wherein the phenyl moiety of said —(CH₂)_(q)-phenyl may optionally besubstituted with one or more substituents independently selected fromthe group consisting of (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms, hydroxy, (C₁-C₆)alkoxyoptionally independently substituted with one or more halo atoms,(C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro,—(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³,—(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G²;—(CH₂)_(q)—NG³SO₂G³ and —(CH₂)_(q)—NG³SO₂—NG¹G²;

Q⁴ is —(CH₂)_(q)—CN, —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², —(CH₂)_(q)CH₂OH,—(CH₂)_(q)CHO, —(CH₂)_(q)—CO—G³, —(CH₂)_(q)—CONG¹G², or a heterocycleselected from —(CH₂)_(q)-thiazolyl, —(CH₂)_(q)-oxazolyl,—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl,—(CH₂)_(q)-1,2,4-oxadiazolyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl;

wherein one of the ring nitrogen atoms of said —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl may optionally besubstituted by (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—CO₂G³, halo, nitro, cyano,—(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²;

Q⁵ is hydrogen or (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

Q⁶ is a covalent bond, oxygen or sulfur;

Q⁷ is hydrogen or (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NH orN—(C₁-C₆)alkyl;

Q¹⁰ is nitro, amino, (C₂-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl,(CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR¹³, (CH₂)_(q)SO₂NR¹¹R¹²,(CH₂)_(q)—NR¹¹SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹),(CH₂)_(q)—O—(CH₂)_(p)CO₂H, (CH₂)_(q)—O—(CH₂)_(p)COR¹³,(CH₂)_(q)—O—(CH₂)_(p)P(O)(OR⁸)(OR⁹), (CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R¹², or(CH₂)_(q)—O—(CH₂)_(p)—NR¹¹SO₂R¹⁰;

R⁸ and R⁹ are each independently hydrogen or (C₁-C₆)alkyl; and

wherein G¹ and G² for each occurrence are each independently hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more halo,(C₁-C₈)alkoxy(C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, or G¹ and G² togetherwith the nitrogen to which they are attached form a saturatedheterocyclic ring having from 3 to 7 carbon atoms wherein one of saidcarbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;

G³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

R¹⁰ for each occurrence is independently (C₁-C₆)alkyl or(C₁-C₆)alkoxy(C₁-C₆)alkyl;

R¹¹ and R¹² are taken separately and, for each occurrence, areindependently hydrogen, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or(C₁-C₆)alkoxy(C₁-C₆)alkyl, or

R¹¹ and R¹² are taken together with the nitrogen atom to which they areattached and form a pyrrolidine, piperidine or morpholine ring whereinsaid pyrrolidine, piperidine or morpholine may optionally be substitutedat any carbon atom by (C₁-C₄)alkyl or (C₁-C₄)alkoxy;

R¹³ for each occurrence is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, NR¹¹R¹², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkylwherein R¹¹ and R¹² are as defined above;

R¹⁴ and R¹⁵ are each independently hydrogen, halo, (C₁-C₆)alkyl, nitro,cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹R¹², COR¹³, CO₂R¹¹,(C₁-C₆)alkoxy, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹ or OR¹¹;

p for each occurrence is independently an integer of 1 to 6; and

q for each occurrence is independently 0 or an integer of 1 to 6;

with the proviso that when Q⁹ is O or S then n is not 0;

with the proviso that when Q¹ is oxygen or sulfur then Q³ is absent; and

with the proviso that when Q² is nitrogen then Q⁵ is absent;

comprising reacting a compound of the formula

wherein R¹ is halo and wherein n, R², R³ and Y are as defined above,with ammonium formate in the presence of palladium-on-carbon.

The present invention further relates to a process wherein a compound ofthe formula

is formed by reacting a compound of the formula

wherein R¹ is hydrogen or halo, and wherein n, R² and Y are as definedabove, with an organic acid anhydride, a dicarbonate or an organic acidchloride.

The present invention further relates to a process wherein thedicarbonate is di-tert-butyl dicarbonate

The present invention further relates to a process wherein the compoundof the formula

is formed by reacting the compound

wherein n, R¹, R² and X are as defined above, with an amine of theformula H₂NY, wherein Y is as defined above, in the presence ofN,N-diisopropylethylamine.

This invention relates to a process for preparing a compound of theformula

wherein n is 0, 1, 2 or 3;

each R² is independently hydrogen, halo, trifluoromethyl, cyano, SR⁴,OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂R⁴;

R⁴ and R⁵, for each occurrence, are each independently selected fromhydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and

wherein the aryl, heterocycloalkyl and heteroaryl groups are optionallysubstituted by one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and

Y is

wherein:

Q¹ is oxygen, nitrogen or sulfur;

Q² is carbon or nitrogen;

Q³ is hydrogen, —(CH₂)_(q)-phenyl, —(C₁ -C₁₀)alkyl, —(CH₂)_(q)—NG¹G²,—(CH₂)_(q)—CO₂G³, —(CH₂)_(q)CO—NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or a heterocycleselected from the group consisting of —(CH₂)_(q)-pyridyl,—(CH₂)_(q)-pyrimidyl, —(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-(1,2,4-oxadiazolyl), —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl;

wherein one of the ring nitrogen atoms of said —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl may optionally besubstituted by (C₁-C₈)alkyl optionally independently substituted withone or more halo atoms;

wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms, nitro,cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G²,—(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl and—(CH₂)_(q)—SO₂NG¹G²;

wherein the phenyl moiety of said —(CH₂)_(q)-phenyl may optionally besubstituted with one or more substituents independently selected fromthe group consisting of (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms, hydroxy, (C₁-C₆)alkoxyoptionally independently substituted with one or more halo atoms,(C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro,—(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³,—(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G²;—(CH₂)_(q)—NG³—SO₂—G³ and —(CH₂)_(q)—NG³—SO₂—NG¹G²;

Q⁴ is —(CH₂)_(q)—CN, —(CH₂)_(q)CO₂G³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², —(CH₂)_(q)CH₂OH,—(CH₂)_(q)—CHO, —(CH₂)_(q)—CO—G³, —(CH₂)_(q)—CONG¹G²; or a heterocycleselected from —(CH₂)_(q)-thiazolyl, —(CH₂)_(q)-oxazolyl,—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl,—(CH₂)_(q)-1,2,4-oxadiazolyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl;

wherein one of the ring nitrogen atoms of said —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl may optionally besubstituted by (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—CO₂G³, halo, nitro, cyano,—(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²;

Q⁵ is hydrogen or (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

Q⁶ is a covalent bond, oxygen or sulfur;

Q⁷ is hydrogen or (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms;

Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NH orN—(C₁-C₆)alkyl;

Q¹⁰ is (CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR¹³,(CH₂)_(q)SO₂NR¹¹R¹², (CH₂)_(q)—NR¹¹SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹),(CH₂)_(q)—O—(CH₂)_(p)CO₂H, (CH₂)_(q)—O—(CH₂)_(p)COR¹³,(CH₂)_(q)—O—(CH₂)_(p)P(O)(OR⁸)(OR⁹), (CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R¹², or(CH₂)_(q)—O—(CH₂)_(p)—NR¹¹SO₂R¹⁰;

R⁸ and R⁹ are each independently hydrogen or (C₁-C₆)alkyl; and

wherein G¹ and G² for each occurrence are each independently hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more halo,(C₁-C₈)alkoxy(C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, or G¹ and G² togetherwith the nitrogen to which they are attached form a saturatedheterocyclic ring having from 3 to 7 carbon atoms wherein one of saidcarbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;

G³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

R¹⁰ for each occurrence is independently (C₁-C₆)alkyl or(C₁-C₆)alkoxy(C₁-C₆)alkyl;

R¹¹ and R¹² are taken separately and, for each occurrence, areindependently hydrogen, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or(C₁-C₆)alkoxy(C₁-C₆)alkyl, or

R¹¹ and R¹² are taken together with the nitrogen atom to which they areattached and form a pyrrolidine, piperidine or morpholine ring whereinsaid pyrrolidine, piperidine or morpholine may optionally be substitutedat any carbon atom by (C₁-C₄)alkyl or (C₁-C₄)alkoxy;

R¹³ for each occurrence is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, NR¹¹R¹², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkylwherein R¹¹ and R¹² are as defined above;

R¹⁴ and R¹⁵ are each independently hydrogen, halo, (C₁-C₆)alkyl, nitro,cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹R¹², COR¹³, CO₂R¹¹,(C₁-C₆)alkoxyl, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹ or OR¹¹;

p for each occurrence is independently an integer of 1 to 6; and

q for each occurrence is independently 0 or an integer of 1 to 6;

with the proviso that when Q⁹ is O or S then n is not 0;

with the proviso that when Q¹ is oxygen or sulfur then Q³ is absent; and

with the proviso that when Q² is nitrogen then Q⁵ is absent;

comprising

(a) reacting the compound of the formula

wherein R¹ is hydrogen or halo, and n, R¹, R², R³ and X are as definedabove, with an amine of the formula H₂NY, wherein Y is as defined above,in the presence of N,N-diisopropylethylamine;

(b) reacting the compound of the formula VII so formed

wherein R¹ is hydrogen or halo and wherein n, R² and Y are as definedabove with an organic acid anhydride, a dicarbonate or an organic acidchloride to form a compound of the formula

wherein n, R¹, R², R⁶ and Y are as defined above and

(c) reacting the compound of formula VI, wherein R¹ is halo, so formedwith ammonium formate in the presence of palladium-on-carbon.

This invention relates to a process for preparing a compound of theformula

wherein n is 0, 1, 2 or 3;

R¹ is hydrogen or halo;

each R² is independently hydrogen, halo, trifluoromethyl, cyano, SR⁴,OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR₄SO₂R⁵ and NR⁴CO₂ R⁴;

R⁴ and R⁵, for each occurrence, are each independently selected fromhydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, and or (C₁-C₆)alkyl; and

wherein the aryl, heterocycloalkyl and heteroaryl groups are optionallysubstituted by one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

comprising reacting a compound of the formula

wherein n, R¹, R² and X are as defined above, with a non-nucleophilicbase.

The present invention further relates to a process wherein thenon-nucleophilic base is sodium hydroxide, potassium hydroxide, sodiumhydride, potassium tert-butoxide or 1,8-diazabicyclo[5.4.0]undec-7-ene.

This invention relates to a compound of the formula

wherein n is 0, 1, 2 or 3;

R¹ is hydrogen or halo;

each R² is independently hydrogen, halo, trifluoromethyl, cyano, SR⁴,OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

R⁴ and R⁵, for each occurrence, are each independently selected fromhydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and

wherein the aryl, heterocycloalkyl and heteroaryl groups are optionallysubstituted by one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above.

The present invention further relates to a compound wherein the compoundof formula XI is the R enantiomer

wherein R¹ is chloro and R² is hydrogen.

The present invention further relates to a compound wherein the compoundof formula XI is the R enantiomer

wherein R¹ and R² are hydrogen.

This invention relates to a compound of the formula

wherein n is 0, 1, 2 or 3;

R¹ is hydrogen or halo;

each R² is independently hydrogen, halo, trifluoromethyl, cyano, SR⁴,OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

R⁴ and R⁵, for each occurrence, are each independently selected fromhydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and

wherein the aryl, heterocycloalkyl and heteroaryl groups are optionallysubstituted by one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above.

The present invention further relates to a compound wherein the compoundof formula XI is the R enantiomer

wherein R¹ is chloro and R² is hydrogen.

The present invention further relates to a compound wherein the compoundof formula XI is the R enantiomer

wherein R¹ and R² are hydrogen.

This invention relates to a compound of the formula

wherein n is 0, 1, 2 or 3;

R¹ is hydrogen or halo;

each R² is independently hydrogen, halo, trifluoromethyl, cyano, SR⁴,OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

R³ is tetrahydrofuranyl, tetrahydropyranyl or a silyl protetcting group;

X is halo, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy,m-nitrobenzenesulfonyloxy or p-nitrobenzenexulfonyloxy;

R⁴ and R⁵, for each occurrence, are each independently selected fromhydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and

wherein the aryl, heterocycloalkyl and heteroaryl groups are optionallysubstituted by one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above.

The present invention further relates to a compound wherein the compoundof formula IX is the R enantiomer

wherein R¹ is chloro; R² is hydrogen; R³ is tert-butyldimethylsilyl; andX is p-toluenesulfonyloxy.

The present invention further relates to a compound wherein the compoundof formula IX is the R enantiomer

wherein R¹ and R²are hydrogen.

This invention relates to a compound of the formula

wherein n is 0, 1, 2 or 3;

m is 1 or 2;

R¹ is hydrogen or halo;

each R² is independently hydrogen, nitro, halo, trifluoromethyl, cyano,SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

R⁴ and R⁵, for each occurrence, are each independently selected fromhydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and

wherein the aryl, heterocycloalkyl and heteroaryl groups are optionallysubstituted by one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above.

The present invention further relates to a compound wherein m is 2, R¹is chloro, and R² is hydrogen.

The present invention further relates to a compound wherein m is 2 andR² and R³ are hydrogen.

The present invention further relates to a compound wherein the compoundof formula XVII is the R enantiomer

wherein m is 2 and R¹ and R² are hydrogen.

The present invention further relates to a compound wherein the compoundof

formula XVII is the R enantiomer

wherein m is 2, R¹ is chloro and R² are hydrogen.

This invention relates to a compound of the formula

wherein R¹ is hydrogen or chloro and BOC is tert-butoxycarbonyl.

This invention relates to a compound of the formula

wherein R¹ is hydrogen or chloro and BOC is tert-butoxycarbonyl.

This invention relates to a compound of the formula

wherein BOC is tert-butoxycarbonyl.

This invention relates to a compound of the formula

wherein R¹ is hydrogen or chloro.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction Scheme illustrates the preparation of thecompounds of the present invention. Unless otherwise indicated n, R¹,R², R³, R⁶, X and Y in the reaction Schemes and the discussion thatfollow are defined as above.

In reaction 1 of Preparation A, the 5-cyanopyridine compound of formulaXIV is converted to the corresponding 5-formylpyridine compound offormula XIII by reacting XIV with a reducing agent, such asdiisobutylaluminum hydride, in the presence of an aprotic solvent, suchas toluene. The reaction is stirred at a temperature range between about0° C. to about 10° C., preferably about 5° C., for a time period betweenabout 15 minutes to about 45 minutes, preferably about 30 minutes. Theresultant intermediate is then hydrolized with an acid or base,preferably methanol and sulfuric acid. The reaction mixture so formed iswarmed to room temperature and stirred for an additional time periodbetween about 30 minutes to about 90 minutes, preferably about 1 hour.

In reaction 2 of Preparation A, the 5-formylpyridine compound of formulaXIII is converted to the corresponding 5-vinylpyridine compound offormula XII by reacting XIII with a methylating reagent, preferablyprepared from methyltriphenylphosphonium bromide and potassiumtert-butoxide, in the presence of a polar aprotic solvent, such astetrahydrofuran. The resulting reaction mixture is stirred for a timeperiod between about 15 minutes to about 45 minutes, preferably about 30minutes, at a temperature range between about −40° C. to about 50° C.,preferably about 5° C.

In reaction 3 of Preparation A, the 5-vinylpyridine compound of formulaXII is converted to the corresponding diol compound of formula XI byreacting XII with a dihydroxylating agent, such as osmium tetroxide orpotassium permanganate, preferably osmium tetroxide, with or without aco-oxidant, such as potassium ferricyanide, hydrogen peroxide, t-butylhydroperoxide or N-methylmorpholine-N-oxide, preferably potassiumferricyanide, in the presence of tert-butanol and water. Such oxidationscan be performed in the presence of a coordinating ligand, such ashydroquinidine 1,4-phthalazinediyl diether or hydroquinine1,4-phthalazinediyl diether, which affords the enantiomerically enricheddiol. The reaction mixture is stirred at a temperature range betweenabout −30° C. to about 10° C., preferably about 5° C., for a time periodbetween about 4 hours to about 18 hours, preferably about 6 hours.

In reaction 4 of Preparation A, the diol compound of formula XI isconverted to the corresponding compound of formula X by reacting XI withthe appropriate sulfonylchloride, such as p-toluenesulfonyl chloride,methanesulfonyl chloride, m-nitrobenzenesulfonyl chloride,p-nitrobenzenesulfonyl chloride or benzenesulfonyl chloride, preferablyp-toluenesulfonyl chloride, in the presence of a base. Suitable baseswhich may be used include lower trialkylamines, pyridine, and pyridinederivatives. Preferred bases include, but are not limited to,triethylamine, diisopropylethylamine, pyridine, 2,4,6-collidine and2,6-lutidine. Pyridine is the most preferred base. It is preferred thatthe solvent is a polar solvent such as (a) an ether derivative,including but not limited to, tetrahydrofuran, dioxane anddimethoxyethane; (b) chlorinated hydrocarbons, including but not limitedto, carbon tetrachloride, chloroform and methylene chloride; (c)aromatic hydrocarbons including but not limited to benzene, toluene andxylene; (d) dimethylformamide; (e) N-methyl-2-pyrrolidinone; (f)dimethylacetamide; or (g) pyridine or any mixture of these solvents.Generally the most preferred solvent is pyridine. The reaction mixtureis stirred at a temperature range between about 0° C. to about 10° C.,preferably about 5° C., for a time period between about 6 hours to about24 hours, preferably about 12 hours. To prepare compounds of formula X,wherein X is halo, the compound of formula XI, wherein X is tosylate, isreacted with a halogenating agent in a reaction inert solvent. Thereaction is carried out at a temperature between 25° C. to the refluxtemperature of the solvent utilized, preferably the reflux temperatureof the solvent. Halogenating agents are compounds which are capable oftransferring an organic substrate having a leaving group, i.e. sylate,which can be displaced by the halide ion. Preferred halogenating agentsare lithium halides, such as lithium chlorides and the preferred solventis a polar protic solvent, such as ethanol.

In reaction 5 of Preparation A, the compound of formula X is convertedto the corresponding compound of formula IX by reacting X with asilyating agent, which include but are not limited totrialkylchlorosilanes, such as tert-butyldimethylsilyl chloride,triethylchlorosilane and triisopropylchlorosilane oralkylarylchlorosilanes, such as diphenylmethylchlorosilane, in thepresence of a base and a polar protic solvent. A preferred silyatingagent is tert-butyldimethylsilyl chloride. Suitable bases include, butare not limited to, triethylamine, N,N-diisopropylethylamine, imidazole,pyridine, 2,6-lutidine and N-methylmorpholine, preferably imidazole.Suitable polar protic solvents include, but are not limited to,dimethylacetamide, tetrahydrofuran, dimethylformamide, methylenechloride and chloroform, preferably dimethylformamide. The reaction iscarried out at a temperature between about 0° C. to about 10° C.,preferably about 5° C., and then warmed to room temperature over a timeperiod between 14 hours to about 22 hours, preferably about 18 hours.

In reaction 1 of Scheme 1, the compound of formula V is converted to thecorresponding compound of formula IV by reacting V with an amine of theformula, H₂NY, in the presence of N, N-diisopropylethylamine and a polaraprotic solvent, such as dimethyl sulfoxide. The reaction is stirred atemperature between 70° C. to about 90° C., preferably about 80° C., fora time period between about 5 hours to about 9 hours, preferably about 7hours.

In reaction 2 of Scheme 1, the compound of formula IV is converted tothe corresponding compound of formula III by reacting IV, wherein R⁶ isan amine protecting group, with an organic acid anhydride, adicarbonate, such as di-tert-butyl dicarbonate or an organic acidchloride. The term “amine protecting group” includes an organic radicalwhich is readily attached to an amine nitrogen atom and which block saidnitrogen atom from reacting with reagents and substrates used in andintermediates and transition state molecules formed in subsequentchemical transformations. The resulting reaction mixture is allowed tostir, at room temperature for a time period between about 2 hours toabout 6 hours, preferably about 4 hours.

In reaction 3 of Scheme 1, the compound of formula III, wherein R¹ ishalo, is converted to the corresponding compound of formula II bytreating III with ammonium formate in the presence ofpalladium-on-carbon and a polar protic solvent, such as methanol. Thereaction is allowed to stir at room temperature for a time periodbetween about 1 hour to about 3 hours, preferably about 2 hours.

In reaction 4 of Scheme 1, the compound of formula II is converted tothe corresponding compound of formula I by treating II withtetra-n-butylammonium fluoride in the presence of an aprotic solvent,such as tetrahydrofuran. The reaction is stirred at room temperature fora time period between about 3 hours to about 12 hours, preferably about8 hours.

In reaction 1 of Scheme 2, the compound of formula VIII is converted tothe corresponding compound of formula VII according to a procedureanalogous to the procedure described above in reaction 1 of Scheme 1.

In reaction 2 of Scheme 2, the compound of formula VII is converted tothe corresponding compound of formula VI according to a procedureanalogous to the procedure described above in reaction 2 of Scheme 1.

In reaction 3 of Scheme 2, the compound of formula VI, wherein R¹ ishalo, is converted to the corresponding compound of formula I accordingto a procedure analogous to the procedure described above in reaction 3of Scheme 1.

In reaction 1 of Scheme 3, the compound of formula X is converted to thecorresponding compound of formula IX by reacting X with anon-nucleophilic base, such as sodium hydroxide, potassium hydroxide,sodium hydride, potassium tert-butoxide or1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is stirred, in areaction inert solvent, at a temperature between about −20° C. to about100° C. The preferred reaction inert solvent is a polar non-hydroxylicsolvent such as an ether derivative including but not limited totetrahydrofuran, dioxane and dimethoxyethane; chlorinated hydrocarbonsincluding but not limited to carbon tetrachloride, chloroform andmethylene chloride; aromatic hydrocarbons including but not limited tobenzene, toluene and xylene; dimethylformamide; dimethylsulfoxide or anymixture of these solvents. Generally the most preferred solvent istetrahydrofuran.

EXAMPLE 1 2-Chloro-5-formylpyridine

To a cooled 5° C., stirred solution of 2-chloro-5-cyanopyridine (25.0grams) in anhydrous toluene (540 mL) was added a 1M solution ofdiisobutylaluminum hydride (189 mL) over a 30 minute period. Theresulting red-colored solution was treated with methanol (50 mL) and 2Msulfuric acid (150 mL), sequentially. The resulting biphasic solutionwas allowed to warm to ambient temperature and stirred for 1 hour. Thereaction mixture was extracted with ethyl acetate, the combined organiclayers were washed with saturated aqueous sodium bicarbonate andsaturated aqueous brine. The organic phase was stirred over activatedcharcoal for 20 minutes, dried over anhydrous sulfate and concentratedin vacuo to afford the title compound as a light-yellow colored solid,23.5 grams ¹H NMR (400 MHz, CDCl₃) δ=10.08 (s, 1H); 8.85 (s, 1H); 8.12(d, 1H); 7.50 (d, 1H).

EXAMPLE 2 2-Chloro-5-vinylpyridine

To a cooled 5° C., stirred slurry of methyltriphenylphosphonium bromide(75.7 grams) in tetrahydrofuran (530 mL) was added potassium t-butoxide(23.8 grams) portionwise over a 5 minute period to produce a yellowslurry. After 30 minutes, 2-chloro-5-formylpyridine (25.0 grams) wasadded in one portion to produce a purple colored slurry. After anadditional 30 minutes, the reaction mixture was treated with saturatedaqueous ammonium chloride (200 mL) and a majority of the tetrahydrofuranwas removed in vacuo. The resulting mixture was washed with ethylacetate, the combined organic layers washed with saturated aqueousbrine, stirred over activated charcoal for 20 minutes, dried overanhydrous sodium sulfate and concentrated in vacuo. The resultingsemi-solid was stirred for 30 minutes with a solution of 2:1 diethylether/petroleum ether (375 mL), filtered and the solids washed with anadditional portion of 2:1 diethyl ether/petroleum ether (300 mL). Thecombined filtrates were concentrated in vacuo, pre-loaded on 60 grams ofsilica gel and chromatographed over 700 grams of silica gel eluting witha gradient of ethyl acetate(0-8%)/hexanes to afford the title compoundas a colorless oil, 15.2 grams ¹H NMR (400 MHz, CDCl₃): δ=8.35 (s, 1H);7.69 (d,1H); 6.65 (dd, 1H); 5.79 (d, 1H); 5.40 (d, 1H).

EXAMPLE 3 (R)-1-(6-Choro-pyridin-3-yl)-ethane-1,2-diol

To a cooled 5° C., stirred slurry of AD_Mix-β® (150 g) in water (530 mL)and t-butanol (450 mL) was added a solution of 2-chloro-5-vinylpyridine(15.0 grams) in t-butanol (80 mL). After 6 hours, solid sodium sulfite(160 grams) was added and the resulting slurry was allowed to stir atambient temperature for 30 minutes. This mixture was extracted withethyl acetate (3 times), the combined organic layers were washed withsaturated aqueous brine, dried over sodium sulfate and concentrated invacuo. The resulting oil was chromatographed on 500 grams of silica geleluting with a gradient of ethyl acetate (70-80%)/hexanes to afford thetitle compound as a colorless oil, 17.8 grams ¹H NMR (400 MHz, CDCl₃):δ=8.35 (s, 1H); 7.71 (d, 1H); 7.30 (d, 1H); 4.85 (dd, 1H); 3.63 (dd,1H).

EXAMPLE 4 (R)-Toluene-4-sulfonic acid2-(6-chloro-pyridin-3-yl)-2-hydroxy-ethyl ester

To a cooled 5° C., stirred solution of(R)-1-(6-chloro-pyridin-3-yl)-ethane-1,2-diol (17.8 grams) in anhydrouspyridine (100 mL) was added p-toluenesulfonyl chloride (19.5 grams) inone portion. After 20 minutes, the cooling bath was removed and stirringwas continued an additional 12 hours. The reaction solution wasconcentrated in vacuo, azeotroped with toluene (2 times), diluted ethylacetate, washed with half-saturated aqueous brine, saturated aqueousbrine, dried over sodium sulfate and concentrated in vacuo. Theresulting solids were recrystallized from ethyl acetate/hexanes toafford the title compound as colorless crystals, 23.3 grams ¹H NMR (400MHz, CDCl₃)=8.29 (s, 1H); 7.72 (d, 2H); 7.64 (d, 1H); 7.32 (d, 2H); 7.28(d, 1H); 5.00 (dd, 1H); 4.09 (AB pattern, 2H); 2.44 (s, 3H).

EXAMPLE 5 (R)-Toluene-4-sulfonic acid2-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-pyridin-3-yl)-ethel ester

To a cooled 5° C., stirred solution of (R)-toluene-4-sulfonic acid2-(6-chloro-pyridin-3-yl)-2-hydroxy-ethyl ester (4.9 grams) andimidazole (2.0 grams) in anhydrous dimethyformamide (14 mL) was addedt-butyldimethylsilyl chloride (2.8 grams). The mixture was allowed towarm to room temperature and stirring was continued for 18 hours. Ethylacetate was added, followed by washing with water (2 times), drying oversodium sulfate and concentrating in vacuo to afford an oil.Chromatography (Flash 40M®) utilizing 10% ethyl acetate/hexanes affordedthe title compound as a colorless oil, 5.6 grams ¹H NMR (400 MHz,CDCl₃): δ=8.24 (s, 1H); 7.64 (d, 2H); 7.56 (d, 1H); 7.28 (d, 2H); 7.23(d,1H); 4.88 (dd, 1H); 3.95 (AB pattern, 2H); 2.44 (s, 3H); 0.83 (s,6H); 0.06 (s, 3H); −0.07 (s, 3H).

EXAMPLE 6[2r-(tert-Butyl-dimethylsilanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl]-[2-(4-nitrophenyl-ethyl]-carbamicacid tert-butyl ester

A solution of (R)-toulene-4-sulfonic acid2-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-pyridin-3-yl)-etyl ester(2.2 grams), 4-nitrophenethylamine (1.6 grams) andN,N-diisopropylethylamine (0.8 grams) in DMSO were heated at 80° C. for7 hours. After cooling, di-t-butyl dicarbonate (2.1 grams) was added andthe resulting solution was stirred at ambient temperature for 4 hours.Ethyl acetate was added, followed by washing with water (2 times),drying over sodium sulfate and concentrating in vacuo to afford oil.Chromatography (Flash 12S®) utilizing 5-10% ethyl acetate/hexanesafforded the title compound as a colorless oil, 1.2.

EXAMPLE 7[2R-(4-Aminophenyl)-ethyl]-[2-(tert-butyl-dimethylsilanyloxy)-2-pyridin-3-yl-ethyl]-carbamicacid tert-butyl ester

To a stirred solution of[2-(tert-butyl-dimethylsilanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl]-[2-(4-nitrophenyl)-ethyl]-carbamicacid tert-butyl ester (0.6 grams) and ammonium formate (1.4 grams) inmethanol (10 mL) was added 10% palladium-on-carbon (0.6 grams). After 2hours, the mixture was filtered through Celite®, the filtrateconcentrated in vacuo and the residue partitioned between ethyl acetateand water. The organic phase was washed with brine, dried over sodiumsulfate and concentrated in vacuo to afford the title compound as ayellow oil, 0.5 grams.

What is claimed is:
 1. A process for preparing a compound of the formula

wherein n is 0, 1, 2 or 3; R¹ is hydrogen or halo; each R² isindependently hydrogen, halo, trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴,OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group is optionallysubstituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵and NR⁴CO₂ R⁴; R³ is tetrahydrofuranyl, tetrahydropyranyl or a silylprotecting group; X is halo, methanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy orp-nitrobenzenesulfonyloxy; R⁴ and R⁵, for each occurrence, are eachindependently selected from hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ isN(R⁴)₂ wherein R⁴ is as defined above; comprising reacting a compound ofthe formula

wherein n, R¹, R² and X are as defined above, with a silyating agent inthe presence of a base.
 2. A process according to claim 1, wherein thesilyating agent is tert butyldimethylsilyl chloride,triethylchlorosilane, triisopropylchlorosilane ordiphenylmethylchlorosilane.
 3. A process according to claim 1, whereinthe base is triethylamine, N,N-diisopropylethylamine, imidazole,pyridine, 2,6-lutidine or N-methylmorpholine.
 4. A process according toclaim 1, wherein the compound of the formula

is formed by reacting a compound of the formula

wherein n, R¹ and R² are as defined above, with a sulfonyl chloride inthe presence of a base, and in the case wherein X is halo, by furthertreatment with a metal halide.
 5. A process according to claim 4,wherein the sulfonyl chloride is p-toluenesulfonyl chloride,methanesulfonyl chloride, m-nitrobenzenesulfonyl chloride,p-nitrobenzenesulfonyl chloride or benezenesulfonyl chloride.
 6. Aprocess according to claim 4, wherein the base is triethylamine,diisopropylethylamine, pyridine, 2,4,6-collidine or 2,6-lutidine.
 7. Aprocess according to claim 4, wherein the metal halide is lithiumchloride.
 8. A process according to claim 4, wherein the compound of theformula

is formed by reacting a compound of the formula

wherein n, R¹ and R² are as defined above, with a dihydroxylating agent,with or without a co-oxidant and/or a coordinating ligand.
 9. A processaccording to claim 8, wherein the dihydroxylating agent is osmiumtetroxide or potassium permanganate.
 10. A process according to claim 8,wherein the co-oxidant is potassium ferricyanide, hydrogen peroxide,tert-butyl hydroperoxide or N-methylmorpholine-N-oxide.
 11. A processaccording to claim 8, wherein the coordinating ligand is hydroquinidine1,4-phthalazinediyl diether or hydroquinine 1,4-phthalazinediyl diether.12. A process according to claim 8, wherein the compound of the formula

is formed by reacting a compound of formula V

wherein n, R¹ and R² are as defined above, with a methylating reagent.13. A process according to claim 12, wherein the methylating reagant isprepared from methyltriphenylphosphonium bromide and potassiumtert-butoxide.
 14. A process according to claim 12, wherein the compoundof the formula

is formed by reducing a compound of the formula

wherein n, R¹ and R² are as defined above, with a reducing agentfollowed by hydrolysis with an acid or base.
 15. A process according toclaim 14, wherein the reducing agent is diisobutylaluminum hydride. 16.A process according to claim 14, wherein the acid is sulfuric acid. 17.A process for preparing a compound of the formula

wherein n is 0, 1, 2 or 3; R¹ is hydrogen or halo; each R² isindependently hydrogen, halo, trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴,OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group is optionallysubstituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵and NR⁴CO₂ R⁴; R³ is tetrahydrofuranyl, tetrahydropyranyl or a silylprotetcting group; X is halo, methanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy orp-nitrobenzenesulfonyloxy; R⁴ and R⁵, for each occurrence, are eachindependently selected from hydrogen, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ isN(R⁴)₂ wherein R⁴ is as defined above; comprising (a) reacting acompound of the formula

wherein n, R¹ and R² as defined above, with a reducing agent followed byhydrolsis with an acid or base; (b) reacting the intermediate of formulaXIII so formed

wherein n, R¹ and R² are as defined above, with a methylating agent toform a vinylpyridine compound of the formula

(c) reacting the vinylpyridine compound so formed in step (b) with adihydroxylating agent, with or without a co-oxidant and/or acoordinating ligand to form the compound of the formula

wherein n, R¹ and R² are as defined above; (d) reacting the compound offormula XI so formed with a sulfonyl chloride in the presence of a baseto form the compound of the formula X

wherein n, R¹, R² and X are as defined above; and (e) reacting thecompound of formula X so formed with silyating agent in the presence ofa base.